Derivatives of 4a 9b - dihydro - 8 9b-dimethyldibenzofuran and of 4a 9b-dihydro - 8 9b-dimethyldibenzofuran-3(4h)-one

ABSTRACT

THIS DISCLOSURE DESCRIBES DERIVATIVES OF 4A,9B-DIHYDRO8,9B-DIMETHYLDIBENZOFURAN AND OF 4A,9B-DIHYDRO-8,9B-DIMETHYLDIBENZOFURAN-3(4H)-ONE USEFUL AS INTERMEDIATES OR AS ANALGESIC AGENTS.

Patented Feb. 29, 1972 3,646,060 Q 0 DERIVATIVES 0F 42,91 DIHYDRO 8,9b-DI- K METHYLDIBENZOFURAN AND OF 4a,9b-DI- 5 HYDRO 8,9b-DIMETHYLDIBENZOFURAN- 5 male 3(4H)-ONE .0 ca, (I) 0 ca, (II 0 H Elizabeth Benz Morlock, Bronx, and Jay Donald Albright and Leon Goldman, Nanuet, N.Y., assignors to American Cyanamid Company, Stamford, Conn. CH3 C 3 No Drawing. Filed May 4, 1970, Ser. No. 34,519 Example Int. Cl. C07d 5/44 10 US. Cl. 260-3263 4 Claims gg? 0 C I Q 0 ABSTRACT OF THE DISCLOSURE COHFNHJCI N {Lows This disclosure describes derivatives of 4a,9b-dihydro- 8,9b-dimethyldibenzofuran and of 4a,9b-dihydro-8,9b-dicII cu methyldibenzofuran-3 (4H)-one useful as intermediates or Example 0 o a as analgetic agents. (v11) CH3 CH5 i. llxample BRIEF SUMMARY OF THE INVENTION 6 ,1

C-NH-COH5 This invention relates to novel derivatives of 4a,9b-di- 0 ii hydro-8,9b-dirnethyldibenzofuran and of 4a,9b-dihydro- 0 CH3 HS-C 8,9b-dimethyldibenzofuran-3 (4H)-one and to methods of preparing these compounds. The novel compounds of the 0 present invention may be represented by the following Example general formulae: (V)

cI-I o H a 0-6-9 Ce s-C B Q 0-11 0 9 5 31 W s- 0-12 0 O CH: 0 CH3 0 CH3 CH3 wherein each conversion is correlated with the correcs sponding specific example appended hereinafter.

Certain of the novel compounds of the present invention (when R is o-bromobenzoyl and R is anilino) are active analgetics when measured by the writhing syndrome test for analgetic activity as described by Siegmund et al., Proc. Soc. Exptl. Biol. Med., vol. 9, p. 729 (1957), with modifications. This method is based upon the reduction of the number of writhes following the intraperitoneal injection of one mg./kg. of body DETAILED DESCRIPTION OF THE INVENTION Weight of phenyl-p-quinone in male Swiss Albino mice The novel compounds of the persent invention are, in Welghmg. 1545 grams mouse T syndrome 18 general, colorless or yellow crystalline solids with charac haracteFlzfid by mtel-{mttent Contracnons of the teristic meltin points and spectral properties They are iwlstmg and of the mink and exte-n of 1 b1 1 t 1k the hind legs beginning 3 to 5 minutes after 1n ect1on so u e m Suc common Orgamc so i S ower a of the phenyl-p-quinone. The test compound is adminnols benzene F i methylene dlchlonde istered orally to groups of two mice each 30 minutes methylformamlfie dlfnethyl Sulfoxlde' They before injection of the phenyl-p-quinone. The total numever, generally lnsoluble in water.

ber of writhes exhibited by each group of mice is re- The novel compounds of the Present ll'lvemlon y be corded for a 3 minute period commencing 15 minutes readily prepared from 4a,9b-dihydro-8,9b-dimethyldiafter injection of the phenyl-p-quinone. A compound is beHZ0f11Ia11-3 9- [Pllmmfifer 6t 3116 considered active if it reduces the total number of (1922); Arkley et al., I. Chem. Soc., 2322 (1956)] in writhes in two test mice from a control value of apaccordance with the following reaction scheme: proximately 30 per pair to a value of 18 or less. In a wherein R is hydrogen, benzoyl or phenylcarbamoyl; R is hydrogen or o-bromobenzoyl; and R is phenyl or anilino.

representative operation, the compounds showed analgetic activity when tested by this procedure at the oral doses indicated in the following table:

Oral dose rng/ kg. Compound of body weight 4 benzoyl 4a,9b dihydro-8,9 b-di.methyl-3- dibenzofuranyl o-bromobenzoate 200 3,4,4a,9a tetrahydro 8,9b dimethyl-3-ox0- 2 dibenzofurancarboxanilide 200 When mixed with suitable excipients or diluents, the above compounds can be prepared as pills, capsules, tablets, powders, solutions, suspensions, and the like for unit dosage and to simplify administration.

The invention will be described in greater detail in conjunction with the following specific examples.

EXAMPLE I Preparation of 1-(4a,9b-dihydro-8,9-b-dimethyl-3- di-benzofuranyl )pyrrolidine CHCl max. 3

6.05 and 6.14;;

EXAMPLE II Preparation of 4a,9bdihydro-8,9b-dirnethyl-3-( lpyrrolidinyl)-4-dibenzofuranyl phenyl ketone To a solution of 0.035 mole of 1-(4a,9b-dihydro-8,9bdimethyl 3 dibenzofuranyl)pyrrolidine, prepared as in Example I, in 200 ml. of benzene was added 4.85 ml. (3.54 g.) of triethylamine and then 4.00 ml. (4.92 g.) of benzoyl chloride. The resulting solution gradually became deep red in color and a gelatinous precipitate separated. The mixture was allowed to stand at room temperature for 20 hours and then was filtered to remove 4.63 g. of triethylamine hydrochloride. Evaporation of the filtrate in vacuo yielded the crude product as a deep red syrup. One-half of this :product was dissolved in benzene and chromatographed on 200 g. of neutral alumina (activity III). Elution with benzene, and evaporation of the eluate yielded 3.27 g. of 4a,9-bdihydro 8,9b dimethyl 3 (l-pyrrolidinyl) 4 dibenzofuranyl phenyl ketone as a deep red syrup,

i2 5? 6.10, 6.19, 6.30 and 6.40,.

EXAMPLE III Preparation of 2 benzoyl-4a,9b-dihydro-8,9b-dimethyldibenzofuran-3 (4H) -one To a solution of 0.816 g. of 4a,9b-dihydro-8,9b-dimethyl 3 (1-pyrrolidinyl) 4 dibenzofuranyl phenyl ketone in 20 ml. of methanol was added 20 ml. of 0.1 N hydrochloric acid and then additional methanol was added to dissolve the precipitated oil. After being allowed to stand for one and a half hours at room temperature the mixture was filtered to yield 0.515 g. of crude product as a tan solid, M.P. 150160 C. Recrystallization from absolute ethanol yielded 0.427 g. of 2benzoyl-4a,9'b-dihydro 8,9b dimethyldi'benzofuran 3(4H) one as oif-white needles, M.P. 165168 C.,

5.95, 6.03, 6.11 and 624a, M52 250 run. (6 3,1150),

A312, NM 350 nm. (6 1,860)

EXAMPLE 1v Preparation of 4a,9b-dihydro-3-hydroxy8,9b-dimethyl- 4-dibenzofuranyl phenyl ketone To a suspension of 0.156 g. of 2-benzoyl-4a,9b-dihydro 8,9b dimethyldibenzofuran 3(4H) one in methanol and concentrated ammonium hydroxide was added chloroform until the solid was dissolved. The resulting two phase mixture was vigorously stirred for 3 hours. The chloroform layer was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residual yellow gum was trit-urated with ether and the resulting suspension was filtered to remove 0.021 g. of starting material. The filtrate was evaporated to dryness under reduced pressure to yield 0.110 g. of 4a,9-b dihydro 3 hydroxy 8,9b dimethyl 4 dibenzofuranyl phenyl ketone as a yellow solid,

NEE, 5.90, 6.06, 6.28 and 6.34;

EXAMPLE V Preparation of 4-benzoyl-4a,9b-dihydro-8,9b-dirnethyl-3- dibenzofuranyl o-bromobenzoate To a solution of 0.00157 mole of 4a,9b-dihydro-3-hydroxy-8,9b-dimethyl 4 dibenzofuranyl phenyl ketone in 10 ml. of pyridine was added 0.345 g. of o-brornobenzoyl chloride. After 18 hours at room temperature the solution was evaporated under reduced pressure and the semi-solid residue was taken up in ether. The filtered solution was evaporated to dryness under reduced pressure to yield a yellow gum which was dissolved in benzene and chromatographed on 10 g. of alumina (activity III). Evaporation of the benzene eluates and crystallization of the yellow residual gums gave 0.169 g. of 4-benzoyl- 4a,9b dihydro-8,9b-dimethyl-3-dibenzofuranyl o-bromobenzoate as colorless crystals, M.P. 118-122 C.,

REE; 5.68, 6.02, 6.20 and 6.27

EXAMPLE VI Preparation of 4a,9b-dihydro-8,9b-dimethyl-3-(1- pyrrolidinyl -4-dibenzofurancarboxanilide To 0.0021 mole of 1-(4a,9b-dihydro-8,9b-dimethy1-3- dibenzofuranyl)pyrro1idine, prepared as in Example I, in ml. of dry benzene was added 2.4 ml. (2.64 g.) of phenyl isocyanate and the solution was allowed to stand at room temperature for 20 hours. The mixture was filtered to yield, after washing with benzene, 2.50 g. of 4a,9b-dihydro 8,9b dimethyl 3 (1-pyrrolidinyl)- 4-dibenzofurancarboxanilide as a yellow solid, M.P. 177 C.,

6.00, 6.10, 6.22 and 6.39;].

EXAMPLE VII Preparation of 3,4,4a,9a-tetrahydro-8,Qb-dimethyl- 3-oxo-2-dibenzofurancarb oxanilide A suspension of 1.50 g. of 4a,9b-dihydro-8,9b-dimethyl- 3 (1 pyrrolidinyl) 4 dibenzofurancarboxanilide in 100 ml. of methanol and 5 ml. of 1 N hydrochloric acid was refluxed with stirring for 4 hours. The cooled solution was evaporated to dryness under reduced pressure to yield a guru as residue. Trituration with water yielded a solid which was collected by filtration and recrystallized from ethanol to yield 0.801 g. of 3,4,4a,9a-tetrahydro- 8,9b-dimethyl 3 oxo 2 dibenzofurancarboxanilide as colorless crystals, M.P. -l97 C.,

5 We claim: 1. A compound of the formula:

6 3. The compound according to claim 1 wherein R is benzoyl; 4a,9b-dihydro-8,9b-dimethyl-3-(1 pyrrolidinyl)- 4-dibenzofuranyl phenyl ketone.

4. The compound according to claim 1 wherein R is 5 phenylcarbamoyl; 4a,9b-dihydro-dimethyl 3 (l-pyrrolidinyl -4-dibenzofurancarboxanilide.

3,252,999 5/1966 Herbst 260346.2

ALEX MAZEL, Primary Examiner wherein R is selected from the group consisting of L NARC AV AGE Assistant Examimr hydrogen, benzoyl and phenylearbamoyl.

1 2. The compound according to claim 1 wherein R 1s 0 US. Cl. X.R.

hydrogen; 1-(4a,9b-dihydro-8,9b-dimethyl 3 dibenzofuranyl)pyrrolidine. 

